Abstract Optimized solid–liquid extraction conditions by response surface methodology (RSM) and optimal solvent selectivity liquid–liquid fractionation by mixture design were studied for process of Pyracantha fortuneana fruits (PFF) healthy products. A combination of total polyphenolic content (TPC), total antioxidant activity (TAA) and chromatographic profiling was used to evaluate the optimization. RSM results were ethanol concentration, 71%; extraction temperature, 51°C; and pH solution, 3.2. The mixture design indicated that the fraction with the highest TAA and TPC was directed to ethyl-acetate phase. The fractions of water-soluble and n-butylalcohol-soluble were rich in TAA and TPC compared with the starting row of PFF. Twenty-seven polyphenols were detected in chromatographic profilings, most of which were reported for the first time in this study. The improvements of accessibility in the optimized fractions suggest their flexible applicabilities for nutraceutical food industries. This study may be crucial approach for all similar natural functional product optimization.